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Antiretroviral Therapy
(Part XXV)

Clinical Implications of Resistance To Antiretroviral Drugs

November 21, 1997

VA Medical Center, San Francisco

Clinical Implications

The dynamics of HIV-1 replication in vivo strongly suggest that early, aggressive antiretroviral therapy is needed to minimize the negative consequences of HIV replication. Recent findings have shown that combinations of potent agents can reduce circulating free virus to undetectable levels in many individuals for prolonged periods of time. A theoretical possibility has also been raised that, in individuals treated at very early stages (i.e., before seroconversion), HIV infection might even be eradicated, because, after some years of theoretical "zero-replication," HIV infection might "burn itself out," as chronically infected cells die off. Long-term data are yet to come, however, and we know that HIV might survive, even in the presence of powerful treatment, within latently infected cells in tissue, bone marrow, and other macrophage-rich tissues and organs, or in "sanctuary sites" inaccessible to treatment.

Indeed, the best opportunity to accomplish maximal suppression of virus replication and to minimize the risk of drug resistance is to use potent combinations in individuals with no prior history of antiretroviral use. However, very early intervention is, unfortunately, not possible for the majority of our patients. Careful therapeutic intervention should therefore be designed with the aim of keeping HIV viral load at undetectable or minimal levels indefinitely to prevent disease progression and transform HIV disease into a chronic disease with minimal levels indefinitely, to prevent disease progression and transform HIV disease into a chronic disease with minimal negative impact on the duration and quality of life of the infected persons.

With that as an aim, then, rational criteria must be adopted for 1) selecting drug combinations with the best chance of long- term efficacy, but also 2) preserving subsequent therapeutic options if the initial choice fails to achieve the desired results.

Because any choice has an impact on later options, therapeutic plan design should include, whenever possible, both initial therapy and predefined alternative antiretroviral regimens. Unfortunately, new resistance mutations continue to be discovered and many of the promising new drugs seem to be better for first-line use. Therefore, the issue of the many patients who are failing agressive antiretroviral regimens remains unsolved.

As far as resistance is concerned, a number of rules should be followed in planning therapeutic strategies:

Clinical Guidelines

    1) Sequential use of combination drugs that share clear cross-resistance phenomena should be avoided.

    2) Potent antiretroviral drugs to which HIV readily develops high-level resistance should not be used in regimens that are expected to yield incomplete suppression of viral replication.

    3) Decisions to alter antiretroviral therapy need to be made carefully, because the number of effective drugs available is still very limited. In fact, an increase in HIV RNA levels in persons receiving fully suppressive antiretroviral therapy can be due to a number of factors, one of which is lack of full adherence to a particular drug combination. In fact, the complexity of the regimens may jeopardize the expected benefits of potent combinations started early. The problem of drug resistance, far from being overcome, might dramatically strike back.

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